Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York, 14853, USA.
Department of Radiology, Washington University School of Medicine, St. Louis, Missouri, 63110, USA.
Dalton Trans. 2024 Sep 10;53(35):14634-14647. doi: 10.1039/d4dt02146k.
Indium-111 (In) is a diagnostic radiometal that is important in nuclear medicine for single-photon emission computed tomography (SPECT). In order to apply this radiometal, it needs to be stably chelated and conjugated to a targeting vector that delivers it to diseased tissue. Identifying effective chelators that are capable of binding and retaining [In]In is an important research area. In this study, two 18-membered macrocyclic chelators, py-macrodipa and py-macrodipa, were investigated for their ability to form stable coordination complexes with In and to be effectively radiolabeled with [In]In. The In complexes of these two chelators were characterized by NMR spectroscopy, X-ray crystallography, and density functional theory calculations. These studies show that both py-macrodipa and py-macrodipa form 8-coordinate In complexes and attain an asymmetric conformation, consistent with prior studies on this ligand class with small rare earth metal ions. Spectrophotometric titrations were carried out to determine the thermodynamic stability constants (log ) of [In(py-macrodipa)] and [In(py-macrodipa)], which were found to be 18.96(6) and 19.53(5), respectively, where the values in parentheses are the errors of the last significant figures obtained from the standard deviation from three independent replicates. Radiolabeling studies showed that py-macrodipa and py-macrodipa can quantitatively be radiolabeled with [In]In at 25 °C within 5 min, even at ligand concentrations as low as 1 μM. The stability of the radiolabeled complexes was investigated in human serum at 37 °C, revealing that ∼90% of [In][In(py-macrodipa)] and [In][In(py-macrodipa)] remained intact after 7 days. The biodistribution of these radiolabeled complexes in mice was investigated, showing lower uptake in the kidneys, liver, and blood at the 24 h mark compared to [In]InCl. These results demonstrate the potential of py-macrodipa and py-macrodipa as chelators for [In]In, suggesting their value for SPECT radiopharmaceuticals.
铟-111（In）是核医学中单光子发射计算机断层扫描（SPECT）中重要的诊断放射性金属。为了应用这种放射性金属，需要将其稳定螯合并与靶向载体结合，将其输送到病变组织。鉴定能够与[In]In 结合并保留其的有效螯合剂是一个重要的研究领域。在这项研究中，研究了两种 18 元大环螯合剂，py-macrodipa 和 py-macrodipa，以考察它们与 In 形成稳定配合物的能力，并有效地用[In]In 标记。通过 NMR 光谱、X 射线晶体学和密度泛函理论计算对这两种螯合剂的 In 配合物进行了表征。这些研究表明，py-macrodipa 和 py-macrodipa 均形成 8 配位的 In 配合物，并获得不对称构象，与先前用小稀土金属离子研究此类配体的研究一致。进行了分光光度滴定以确定[In(py-macrodipa)]和[In(py-macrodipa)]的热力学稳定常数（log K），分别为 18.96(6)和 19.53(5)，括号中的值是从三个独立重复实验的标准偏差获得的最后有效位数的误差。放射性标记研究表明，即使在低至 1 μM 的配体浓度下，py-macrodipa 和 py-macrodipa 也可以在 25°C 下在 5 分钟内定量地用[In]In 标记，放射性标记配合物的稳定性在 37°C 下的人血清中进行了研究，结果表明，[In][In(py-macrodipa)]和[In][In(py-macrodipa)]在 7 天后仍保持 90%以上的完整性。这些放射性标记配合物在小鼠中的生物分布研究表明，与[In]InCl 相比，在 24 小时标记时肾脏、肝脏和血液中的摄取量较低。这些结果表明，py-macrodipa 和 py-macrodipa 作为[In]In 的螯合剂具有潜力，表明它们对 SPECT 放射性药物具有价值。
